title: Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β-cells.
abstract: The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in β-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in β-cells. GKA administration improved β-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in β-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in β-cell apoptosis, compared with Akita mice. β-cell-specific IRS-2-overexpressing (βIRS-2-Tg) Akita mice showed less β-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but βIRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against β-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in β-cells.
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Togashi
authors.forename: Eri
authors.initials: E
authors.lastname: Sakamoto
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kaji
authors.forename: Kazuki
authors.initials: K
authors.lastname: Tajima
authors.forename: Kazuki
authors.initials: K
authors.lastname: Orime
authors.forename: Hideaki
authors.initials: H
authors.lastname: Inoue
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000628:therapy; D059865:Endoplasmic Reticulum Stress; D005434:Flow Cytometry; D005941:Glucokinase / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D040081:Protein Array Analysis; D060888:Real-Time Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D051742:Transcription Factor CHOP; D005941:Glucokinase